ABSTRACT Oropharyngeal cancer has been increasing in incidence in the United States since 1970, while other head and neck cancers are becoming less common. The factors responsible for this change are: 1) infection with high risk human papillomaviruses (hrHPV) leading to virally-induced tonsil and base of tongue cancers and; 2) reduced cigarette smoking that is beginning to have an impact on the incidence of oral and laryngeal cancer. Most HPV- positive oropharynx cancers respond well to intensive therapy consisting of concurrent chemotherapy and intensity modulated radiation (IMRT). The high response rate (70-80% in most series) and the high morbidity (swallowing problems and neuropathies) of current therapy have stimulated interest in deescalating treatment intensity for HPV-positive oropharynx cancers. Notably, even with intensive treatment 20-30% of the patients progress to lethal recurrent or metastatic disease. The excellent response rates may fall substantially with less aggressive treatment. Thus, it is critical to understand the molecular mechanisms that determine tumor behavior and response to therapy. We will test these hypotheses: 1) we postulate that tumors driven predominantly by the HPV oncogenes, E6 and E7, are those tumors most likely to be managed by low morbidity strategies; 2) we postulate that HPV integration within a cellular gene increases the risk of recurrent and metastatic disease; and 3) we postulate that HPV-positive tumors that have additional genetic aberrations are the most resistant to current therapy and will require alternative treatment. Thus, we are investigating molecular characteristics of the tumor, the virus and the cellular genome of HPV-induced cancers to determine those factors that identify the genetic characteristics that differentiate tumors that progress from those that respond, and to identify targetable molecular changes. We postulate that tumors driven only by the viral oncogenes may be susceptible to a variety of low morbidity treatments. Integration into a cancer related gene may increase likelihood of progression but may also identify a potentially targetable pathway. Tumors with additional molecular drivers or lost control mechanisms may be the most likely to recur or metastasize, but may also have targetable pathways. These concepts can be tested by future trials once the biomarkers are known. In this project we will investigate HPV integration site, viral oncogene expression and alternate transcripts, effects of integration on cellular gene expression, and we will characterize other genetic abnormalities that correlate with outcome. Preliminary data support our hypotheses and from this work we hope to develop individualized treatment most appropriate for each patient with HPV-positive oropharyngeal cancer. We have discovered that viral oncogene-to host cell gene fusions are associated with poor outcome and that transcripts from these can be isolated. In the minority Supplement Dr. Lorenzatti-Hiles will determine the role of these fusion transcripts in cancer progression.